Pharmaceuticals are often formulated from crystalline compounds because crystalline materials often provide high levels of purity and are resistant to chemical instability under ambient conditions. Crystalline materials of a single chemical species with a common molecular structure may exist in more than one polymorphic form. Polymorphic forms are differing packing arrangements of the same molecular species, i.e., the same chemical substance at the molecular level. Polymorphs differ only at the level of the crystalline solid. The translational repeating unit in the structure of a crystal is the unit cell. Two polymorphic forms may have crystallographic unit cells that differ in number of molecules in the unit cell and in volume or and, most importantly to us, in the value of the volume per molecule. Two polymorphic forms of the same chemical substance can differ in density.
U.S. Pat. No. 6,965,832 “Investigating different physical and/or chemical forms of materials” describes formation of distinguishable crystals but it does not involve their physical separation. This patent also includes a detailed description of the current state of the art.
U.S. Pat. No. 6,965,832 claims (see claim 1, column 14, line 14) that the invention is comprised of “providing an array of receptacles each containing material (hereinafter ‘said initial material”) to be investigated; subjecting said initial material in respective different receptacles to respective different treatments under the control of a computer; and analyzing any material resulting from said different treatments (hereinafter ‘said resultant material’)” (underline added). All subsequent claims refer to claim 1 either directly or indirectly. The methods of treatment enumerated are variations in solvent, other chemical additives especially salt forming materials, pressure to retain solvent or time of treatment, temperature, heating or cooling and cycles of same. The need for distinct treatments is inherent to this method due to lack of physical separation.
U.S. Pat. No. 6,709,871, “Precision Fluid Gradient Formation” provides a detailed and in-depth review of the state of the art and the history of the technology of formation of liquid density gradients. The terms “polymorph” and “crystal” do not appear in this patent.
U.S. Pat. No. 6,709,871 refers only to separation of cells. “Pharmaceutical” is mentioned only in respect to the use of cells separated by this method in testing of said pharmaceuticals. The method and the device used in U.S. Pat. No. 6,709,871 is designed for use with aqueous solvents and for relatively low densities appropriate to the separation involved.
There is a need for systems and methods that will unambiguously permit the enumeration and characterization of polymorphic forms present in a sample of crystallized active pharmaceutical ingredient or, more generally, in a pharmaceutical preparation containing the active pharmaceutical ingredient.